2-oxo-1,3-oxazolidinyl imidazothiadiazole derivatives

ABSTRACT

The present invention relates to 2-oxo-1,3-oxazolidinyl imidazothiadiazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.

INTRODUCTION

The present invention relates to 2-oxo-1,3-oxazolidinylimidazothiadiazole derivatives, processes for preparing them,pharmaceutical compositions containing them and their use aspharmaceuticals.

A persistent problem in seizure control arises with those patients whodo not at all or only insufficiently respond to currently availabletreatments. Those patients are viewed as being refractory to treatmentand represent a considerable challenge for the medical community. It isestimated that about 30% of epilepsy patients are to be classified asbeing refractory. Hence, there is a need to develop new medications thatspecifically target this population of patients.

Anti-epileptic compounds of formula (A) are disclosed in WO 2008/132139:

wherein

Y is O or S;

R¹ is hydrogen or C₁₋₆ alkyl;R² is hydrogen;R³ is —CONR⁵R⁶, —COR⁷, an imidazolyl, an imidazopyridinyl, animidazopyridazinyl;R⁵, R⁶ are the same or different and are independently selected fromhydrogen and C₁₋₆ alkyl;R⁷ is C₁₋₆ alkyl;

Z is a monocyclic or bicyclic heterocyclic moiety selected from thegroup consisting of imidazolidin-1-yl, 1,3-oxazolidin-3-yl,2,5-dihydro-1H-pyrrol-1-yl, 1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl,piperidin-1-yl, azepan-1-yl, 5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl.

In a specific embodiment of WO 2008/132139 the Z═Y moiety in formula (A)could be:

wherein X is O or S.

Anti-epileptic compounds of formula (I) are disclosed in WO 2011/047860:2-oxo-1-pyrrolidinyl imidazothiadiazole derivatives according to formula(I)

whereinR¹ is a C₁₋₄ alkyl containing at least one halogen substituent;R² is either a halogen (chlorine, bromine, iodine) or a C₁₋₄ alkylcontaining at least one halogen substituent;R³ is a C₁₋₄ alkyl (e.g. a methyl or ethyl) containing at least onehydroxy (OH) or an alkoxy (e.g. methoxy or ethoxy or propoxy)substituent.

Anti-epileptic compounds of formula (I) are disclosed in WO 2012/143116:4-oxo-1-imidazolidinyl imidazothiadiazole derivatives according toformula (I),

whereinR¹ is a C₁₋₄ alkyl optionally substituted by one or more (1 to 6,preferably 2, 3 or 5) halogens, by a substituted or unsubstituted phenylor by a substituted or unsubstituted C₁₋₄ cycloalkyl;R² is either a halogen (chlorine, bromine, iodine) or a C₁₋₄ alkylcontaining one or more (i.e. 1, 2 or 3) halogen substituents;R³ is a C₁₋₄ alkyl (e.g. a methyl or ethyl) containing at least onehydroxy (OH) or an alkoxy (e.g. methoxy or ethoxy or propoxy)substituent.

The invention provides new 2-oxo-1,3-oxazolidinyl imidazothiadiazolederivatives having the formula (I), their geometrical isomers,enantiomers, diastereoisomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

Further aspects of the invention will become apparent from the detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 2-oxo-1,3-oxazolidinylimidazothiadiazole derivatives according to formula (I),

whereinR¹ is a C₁₋₄ alkyl optionally substituted by one or more halogensubstituents;R² is a halogen atom or a C₁₋₄ alkyl optionally substituted by one ormore halogen atoms;R³ is a C₁₋₄ alkyl substituted by an alkoxy substituent.

Also comprised are tautomers, geometrical isomers, enantiomers,diastereomers, isotopes and mixtures, or a pharmaceutically acceptablesalt of compounds of formula (I) as well as any deuterated variant.

In specific embodiment, R¹ is an i-butyl, a n-propyl, a2,2-difluoropropyl, a 2-chloro-2,2-difluoroethyl, a 2,2-difluoroethyl, a2,2,2-trifluoroethyl or a 2-fluoroethyl moiety.

In a more specific embodiment, R¹ is a n-propyl, a2-chloro-2,2-difluoroethyl, a 2,2-difluoropropyl or a2,2,2-trifluoroethyl moiety.

Preferably, R¹ is a 2,2-difluoropropyl, a 2,2,2-trifluoroethyl or an-propyl moiety.

In a further specific embodiment, R² is a chlorine atom, adifluoromethyl moiety, or a trifluoromethyl moiety.

In a preferred embodiment, R² is a difluoromethyl moiety or atrifluoromethyl moiety.

In a further specific embodiment, R³ is methoxymethyl, a[(²H₃)methyloxy]methyl, a methoxy(²H₂)methyl, or a[(²H₃)methyloxy](²H₂)methyl moiety.

In a preferred embodiment, R³ is a methoxymethyl moiety.

In a further specific embodiment, compounds of formula (I) are thosewherein:

-   -   R¹ is a n-propyl moiety, a 2-chloro-2,2-difluoroethyl, a        2,2-difluoropropyl or a 2,2,2-trifluoroethyl moiety;    -   R² is a chlorine atom, a difluoromethyl, or a trifluoromethyl        moiety;    -   R³ is a methoxymethyl, a [(²H₃)methyloxy]methyl, a        methoxy(²H₂)methyl, or a [(²H₃)methyloxy](²H₂)methyl moiety.

In a further specific embodiment, compounds of formula (I) are thosewherein:

-   -   R¹ is a n-propyl moiety; a 2,2-difluoropropyl or a        2,2,2-trifluoroethyl moiety    -   R² is a difluoromethyl or a trifluoromethyl moiety;    -   R³ is a methoxymethyl, a [(²H₃)methyloxy]methyl, a        methoxy(²H₂)methyl or a [(²H₃)methyloxy](²H₂)methyl moiety.

In a preferred embodiment, compounds of formula (I) are those wherein:

-   -   R¹ is a n-propyl moiety; a 2,2-difluoropropyl or a        2,2,2-trifluoroethyl moiety;    -   R² is a difluoromethyl or a trifluoromethyl moiety;    -   R³ is a methoxymethyl moiety.

Specific compounds of the present invention are those selected from thegroup consisting of:

-   (+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;-   (+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;-   (+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;-   (+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;-   (+)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;-   (+)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;-   (+)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;-   (+)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;-   (+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one;-   (+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one;-   (+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one;-   (+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one;-   (−)-5-(2,2-difluoropropyl)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one;-   (+)-5-(2,2-difluoropropyl)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one;-   3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2-difluoropropyl)oxazolidin-2-one,    enantiomer 1;-   3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2-difluoropropyl)oxazolidin-2-one,    enantiomer 2.

The compounds of the present invention are for use as a medicament, inthe treatment of epilepsy, epileptogenesis, seizure disorders,convulsions, in particular for refractory seizures.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly throughout the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“C₁₋₄ alkyl” refers to alkyl groups having 1 to 4 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl. “C₁₋₄ alkyl” groups may besubstituted by one or more substituents selected from halogen, oralkoxy.

Any moiety “H” in formula (I) may be the isotope hydrogen, deuterium ortritium.

“Alkoxy” refers to the group —O—R where R includes “C₁₋₄ alkyl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms, preferablyfluoro and chloro.

The “pharmaceutically acceptable salts” according to the inventioninclude therapeutically active, non-toxic acid or base salt forms whichthe compounds of formula (I) are able to form.

The acid addition salt form of a compound of formula (I) that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula (I) and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Compounds of formula (I) and/or their intermediates may have at leastone stereogenic center in their structure. This stereogenic center maybe present in a R or a S configuration, said R and S notation is used incorrespondence with the rules described in Pure Appl. Chem., 45 (1976)11-30. The invention thus also relates to all stereoisomeric forms suchas enantiomeric and diastereoisomeric forms of the compounds of formula(I) or mixtures thereof (including all possible mixtures ofstereoisomers). With respect to the present invention reference to acompound or compounds is intended to encompass that compound in each ofits possible isomeric forms and mixtures thereof, unless the particularisomeric form is referred to specifically. The expression“enantiomerically pure” as used herein refers to compounds which haveenantiomeric excess (ee) greater than 95%.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of formula (I) according to the invention can be preparedanalogously to conventional methods as understood by the person skilledin the art of synthetic organic chemistry.

According to one embodiment, compounds having the general formula (I)may be prepared by reaction of a compound of formula (II) with an ureaof formula (III) according to the equation:

wherein R¹, R² and R³ have the same definitions as defined above forcompounds of formula (I).

This reaction may be performed using an acid such as p-toluenesulfonicacid in an aprotic solvent such as sulfolane at high temperature.

Compounds of formula (II) may be prepared by hydroxymethylation of acompound of formula (IV) according to the equation:

wherein R² and R³ have the same definition as defined above forcompounds of formula (I).

This reaction may be performed using a formylating agent such asparaformaldehyde under acidic conditions in a polar solvent such asdioxane at 100° C., or according to any other method known to the personskilled in the art.

Compounds of formula (IV) may be synthesized by reaction of a compoundof formula (V) with a bromo derivative of formula (VI) according to theequation:

wherein R² and R³ have the same definition as described above forcompounds of formula (I).

This reaction can be performed using procedures described in theliterature or known to the person skilled in the art.

Compounds of formula (V) and compounds of formula (VI) are eithercommercially available or may be synthesized according to any methodknown to the person skilled in the art.

According to one embodiment, compounds of formula (III) may be preparedby cyclization of a compound of formula (VII) according to the equation:

This reaction may be performed with 1,1′-carbonyldiimidazole in a polarsolvent such as tetrahydrofuran in the presence of a base such as sodiumhydride at room temperature or using procedures known to the personskilled in the art.

Compounds of formula (VII) may be prepared by reduction of a compound offormula (VIII) according to the equation

wherein R¹ has the same definition as defined above.

This reaction may be performed using a reducing agent such as, but notlimited to, hydrogen in the presence of a catalyst such as palladium oncharcoal in a polar solvent such as ethanol or by other procedures knownto the person skilled in the art.

Compounds of formula (VIII) may be prepared starting from commerciallyavailable aldehydes or alcohols wherein R¹ has the same definition asdefined above according to any reaction sequence known to the personskilled in the art.

The compounds of the present invention are for use as a medicament, inthe treatment of epilepsy, epileptogenesis, seizure disorders,convulsions, in particular for refractory seizures.

Seizures can be classified as refractory when a patient fails to achieveseizure freedom for 12 months or more of state of the art treatment withtwo or more anti-epileptic drugs at maximal tolerated doses. TheInternational League Against Epilepsy (ILAE) has defined drug resistantepilepsy as “failure of adequate trials of two tolerated andappropriately chosen and used AED schedules (whether as monotherapies orin combination) to achieve sustained seizure freedom”.

The methods of the invention comprise administration to a mammal(preferably a human) suffering from above mentioned conditions ordisorders, of a compound according to the invention in an amountsufficient to alleviate or prevent the disorder or condition.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing 1 to 2000 mg,preferably 1 to 1000 mg, more preferably 1 to 500 mg of activeingredient per unit dosage form.

The term “treatment” as used herein includes curative treatment andprophylactic treatment.

By “curative” is meant efficacy in treating a current symptomaticepisode of a disorder or condition.

By “prophylactic” is meant prevention of the occurrence or recurrence ofa disorder or condition.

The term “epilepsy” as used herein refers to a chronic neurologiccondition characterised by unprovoked, recurrent epileptic seizures. Anepileptic seizure is the manisfestation of an abnormal and excessivesynchronised discharge of a set of cerebral neurons; its clinicalmanifestations are sudden and transient. The term “epilepsy” as usedherein can also refer to a disorder of brain function characterised bythe periodic occurrence of seizures. Seizures can be “nonepileptic” whenevoked in a normal brain by conditions such as high fever or exposure totoxins or “epileptic” when evoked without evident provocation.

The term “seizure” as used herein refers to a transient alteration ofbehaviour due to the disordered, synchronous, and rhythmic firing ofpopulations of brain neurones.

A further aspect of the present invention relates to a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)in combination with a pharmaceutically acceptable diluent or carrier.

Activity in any of the above-mentioned indications can of course bedetermined by carrying out suitable clinical trials in a manner known toa person skilled in the relevant art for the particular indicationand/or in the design of clinical trials in general.

For treating diseases, compounds of formula (I) or theirpharmaceutically acceptable salts may be employed at an effective dailydosage and administered in the form of a pharmaceutical composition.

Therefore, another embodiment of the present invention concerns apharmaceutical composition comprising an effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof incombination with a pharmaceutically acceptable diluent or carrier.

To prepare a pharmaceutical composition according to the invention, oneor more of the compounds of formula (I) or a pharmaceutically acceptablesalt thereof is intimately admixed with a pharmaceutical diluent orcarrier according to conventional pharmaceutical compounding techniquesknown to the skilled practitioner.

Suitable diluents and carriers may take a wide variety of formsdepending on the desired route of administration, e.g., oral, rectal,parenteral or intranasal.

Pharmaceutical compositions comprising compounds according to theinvention can, for example, be administered orally, parenterally, i.e.,intravenously, intramuscularly or subcutaneously, intrathecally,transdermally (patch), by inhalation or intranasally.

Pharmaceutical compositions suitable for oral administration can besolids or liquids and can, for example, be in the form of tablets,pills, dragees, gelatin capsules, solutions, syrups, chewing-gums andthe like.

To this end the active ingredient may be mixed with an inert diluent ora non-toxic pharmaceutically acceptable carrier such as starch orlactose. Optionally, these pharmaceutical compositions can also containa binder such as microcrystalline cellulose, gum tragacanth or gelatine,a disintegrant such as alginic acid, a lubricant such as magnesiumstearate, a glidant such as colloidal silicon dioxide, a sweetener suchas sucrose or saccharin, or colouring agents or a flavouring agent suchas peppermint or methyl salicylate.

The invention also contemplates compositions which can release theactive substance in a controlled manner.

Pharmaceutical compositions which can be used for parenteraladministration are in conventional form such as aqueous or oilysolutions or suspensions generally contained in ampoules, disposablesyringes, glass or plastics vials or infusion containers.

In addition to the active ingredient, these solutions or suspensions canoptionally also contain a sterile diluent such as water for injection, aphysiological saline solution, oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents, antibacterial agents suchas benzyl alcohol, antioxidants such as ascorbic acid or sodiumbisulphite, chelating agents such as ethylene diamine-tetra-acetic acid,buffers such as acetates, citrates or phosphates and agents foradjusting the osmolarity, such as sodium chloride or dextrose.

These pharmaceutical forms are prepared using methods which areroutinely used by pharmacists.

The amount of active ingredient in the pharmaceutical compositions canfall within a wide range of concentrations and depends on a variety offactors such as the patient's sex, age, weight and medical condition, aswell as on the method of administration. Thus the quantity of compoundof formula (I) in compositions for oral administration is at least 0.5%by weight and can be up to 80% by weight with respect to the totalweight of the composition.

In accordance with the invention it has also been found that thecompounds of formula (I) or the pharmaceutically acceptable saltsthereof can be administered alone or in combination with otherpharmaceutically active ingredients. Non-limiting examples of suchadditional compounds which can be cited for use in combination with thecompounds according to the invention are antivirals, antispastics (e.g.baclofen), antiemetics, antimanic mood stabilizing agents, analgesics(e.g. aspirin, ibuprofen, paracetamol), narcotic analgesics, topicalanesthetics, opioid analgesics, lithium salts, antidepressants (e.g.mianserin, fluoxetine, trazodone), tricyclic antidepressants (e.g.imipramine, desipramine), anticonvulsants (e.g. valproic acid,carbamazepine, phenytoin), antipsychotics (e.g. risperidone,haloperidol), neuroleptics, benzodiazepines (e.g. diazepam, clonazepam),phenothiazines (e.g. chlorpromazine), calcium channel blockers,amphetamine, clonidine, lidocaine, mexiletine, capsaicin, caffeine,quetiapine, serotonin antagonists, β-blockers, antiarrhythmics,triptans, ergot derivatives and amantadine.

For oral compositions, the daily dosage is in the range 1 mg to 2000 mgof compounds of formula (I). Preferably in the range 1 mg to 1000 mg ofcompounds of formula (I), most preferably 1 mg to 500 mg.

In compositions for parenteral administration, the quantity of compoundof formula (I) present is at least 0.5% by weight and can be up to 33%by weight with respect to the total weight of the composition. For thepreferred parenteral compositions, the dosage unit is in the range 1 mgto 2000 mg of compounds of formula (I).

The daily dose can fall within a wide range of dosage units of compoundof formula (I) and is generally in the range 1 to 2000 mg, preferably 1to 1000 mg. However, it should be understood that the specific doses canbe adapted to particular cases depending on the individual requirements,at the physician's discretion.

The SV2 proteins binding compounds provided by this invention andlabeled derivatives thereof may be useful as standards and reagents indetermining the ability of tested compounds (e.g., a potentialpharmaceutical) to bind to the SV2 proteins.

Labeled derivatives of SV2 proteins' ligands provided by this inventionmay also be useful as radiotracers for positron emission tomography(PET) imaging or for single photon emission computerized tomography(SPECT).

The present invention therefore further provides labelled ligands astools to screen chemical libraries for the discovery of potentialpharmaceutical agents, in particular for treatment and prevention of theconditions set forth herein, on the basis of more potent binding to SV2proteins, for localizing SV2 proteins in tissues, and for characterizingpurified SV2 proteins. SV2 proteins include SV2A, SV2B, and SV2C wherebySV2A is the binding site for the anti-seizure drug levetiracetam and itsanalogs. The SV2 isoforms SV2A, SV2B, or SV2C can be derived fromtissues, especially brain, from any mammal species, including human, rator mice. Alternately the isoforms may be cloned versions of anymammalian species, including human, rat, and mice, heterologouslyexpressed and used for assays. The screening method comprises exposingbrain membranes, such as mammalian or human brain membranes, or celllines expressing SV2 proteins or fragments thereof, especially SV2A andSV2C, but including SV2B, to a putative agent and incubating themembranes or proteins or fragments and the agent with labelled compoundof formula (I). The method further comprises determining if the bindingof the compound of formula (I) to the protein is inhibited by theputative agent, thereby identifying binding partners for the protein.Thus, the screening assays enable the identification of new drugs orcompounds that interact with SV2 proteins. The present invention alsoprovides photoactivable ligands of SV2 proteins.

The labelled-ligands can also be used as tools to assess theconformation state of SV2 proteins after solubilization, purificationand chromatography. The labelled-ligands may be directly or indirectlylabeled. Examples of suitable labels include a radiolabel, such as ³H, afluorescent label, an enzyme, europium, biotin and other conventionallabels for assays of this type.

Labelled compounds of formula (I) are useful in the methods as probes inassays to screen for new compounds or agents that bind to the SV2proteins (SV2A, SV2B and SV2C). In such assay embodiments, ligands canbe used without modification or can be modified in a variety of ways;for example, by labelling, such as covalently or non-covalently joininga moiety which directly or indirectly provides a detectable signal. Inany of these assays, the materials can be labelled either directly orindirectly. Possibilities for direct labelling include label groups suchas: radiolabels including, but not limited to, [³H], [¹⁴C], [³²P], [³⁵S]or [¹²⁵I], enzymes such as peroxidase and alkaline phosphatase, andfluorescent labels capable of monitoring the change in fluorescenceintensity, wavelength shift, or fluorescence polarization, including,but not limited to, fluorescein or rhodamine. Possibilities for indirectlabelling include biotinylation of one constituent followed by bindingto avidin coupled to one of the above label groups or the use ofanti-ligand antibodies. The compounds may also include spacers orlinkers in cases where the compounds are to be attached to a solidsupport. To identify agents or compounds which compete or interact withlabelled ligands according to the invention for binding to the SV2proteins (especially SV2A and SV2C), intact cells, cellular or membranefragments containing SV2A or SV2C or the entire SV2 protein or afragment thereof can be used. The agent or compound may be incubatedwith the cells, membranes, SV2 protein or fragment prior to, at the sametime as, or after incubation with labelled levetiracetam or an analog orderivative thereof. Assays may be modified or prepared in any availableformat, including high-throughput screening (HTS) assays that monitorthe binding of levetiracetam or the binding of derivatives or analogsthereof to SV2 proteins or fragments thereof. In many drug screeningprograms which test libraries of compounds, high throughput assays aredesirable in order to maximize the number of compounds surveyed in agiven period of time. Such screening assays may use intact cells,cellular or membrane fragments containing SV2 as well as cell-free ormembrane-free systems, such as may be derived with purified orsemi-purified proteins. The advantage of the assay with membranefragment containing SV2 or purified SV2 proteins and peptides is thatthe effects of cellular toxicity and/or bioavailability of the testcompound can be generally ignored, the assay instead being focusedprimarily on the effect of the drug on the molecular target as may bemanifest in an inhibition of, for instance, binding between twomolecules. The assay can be formulated to detect the ability of a testagent or compound to inhibit binding of labeled ligand according to theinvention to SV2 or a fragment of SV2 or of labelled levetiracetam, orderivatives or analogs thereof, to SV2 or a fragment of SV2 protein. Theinhibition of complex formation may be detected by a variety oftechniques such as filtration assays, Flashplates (Perkin Elmer),scintillation proximity assays (SPA, GE). For high-throughput screenings(HTS), scintillation proximity assay which uses microspheres coated withbiological membranes or flashplates coated with biological membranes arepowerful methods that do not require separation or washing steps.

A problem which can be faced when developing compounds for use intherapy is the capacity of certain compounds (perpetrator drugs), whichcould be co-administered together with the compounds of the presentinvention (victim drugs), to induce CYP450 enzymes, in particularCYP3A4/5. The induction of such enzymes by the perpetrator drugs mayimpact the exposure of the victim drug, when mainly metabolized byCYP450 enzymes and CYP3A4/5 in particular, thereby potentially alteringtheir efficacy profile. It is therefore desirable to develop compoundswith limited potential for metabolization by CYP3A4/5 enzymes.

The CYP3A4/5 contribution to the total metabolism of compounds accordingto the present invention has been evaluated by calculating the ratiobetween human hepatocytes clearances in absence and presence of aselective CYP3A4/5 inhibitor such as azamulin.

When tested in this assay according to the protocol described in thepresent patent application, compounds according to the present inventionexhibit a fraction metabolized by CYP3A4/5 (F_(m,CYP3A4/5)) typicallylower than 40%, therefore minimizing the risk for drug-drug interactionswhen coadministered with CYP450 inducers.

EXPERIMENTAL SECTION Abbreviations/Recurrent Reagents

Ac: acetyl

ACN: Acetonitrile

Brine: Saturated aqueous sodium chloride solutionnBu: n-butyltBu: tert-butylBz: benzoylCV: column volumes

DCM: Dichloromethane DMF: N,N-Dimethylformamide DMSO: DimethylsulfoxideEt: Ethyl EtOH: Ethanol

Et₂O: Diethyl etherEtOAc: Ethyl acetate

h: Hour HPLC: High Pressure Liquid Chromatography LC: LiquidChromatography LCMS: Liquid Chromatography Mass Spectrometry MeOH:Methanol

min.: minutesNMR: Nuclear magnetic resonancePrOH: isopropanolPTSA: p-toluenesulfonic acidRT: room temperature

SFC: Supercritical Fluid Chromatography THF: Tetrahydrofuran TLC: ThinLayer Chromatography

In the present application, the IUPAC name (or the name generated fromAccelerys Draw 4.0) of the compounds is mentioned.

Analytical Methods

All reactions involving air or moisture-sensitive reagents wereperformed under a nitrogen or argon atmosphere using dried solvents andglassware. Experiments requiring microwave irradiation are performed ona Biotage Initiator Sixty microwave oven upgraded with version 2.0 ofthe operating software. Experiments are run to reach the requiredtemperature as quickly as possible (maximum irradiation power: 400 W, noexternal cooling). Commercial solvents and reagents were generally usedwithout further purification, including anhydrous solvents whenappropriate (generally Sure-Seal™ products from Aldrich Chemical Companyor AcroSeal™ from ACROS Organics). In general reactions were followed bythin layer chromatography, HPLC or mass spectrometry analyses.

HPLC analyses are performed using an Agilent 1100 series HPLC systemmounted with a Waters XBridge MS C18, 5 pm, 150×4.6 mm column. Thegradient runs from 100% solvent A (water/ACN/ammonium formate solution85/5/10 (v/v/v)) to 100% solvent B (water/ACN/ammonium formate solution5/85/10 (v/v/v) in 6 min. with a hold at 100% B of 5 minutes. The flowrate is set at 8 mL/min during 6 min. then increased at 3 mL/min during2 min. with a hold at 3 mL/min during 3 minutes. A split of 1/25 is usedjust before API source. The chromatography is carried out at 45° C. Theammonium formate solution (pH-8.5) is prepared by dissolution ofammonium formate (630 mg) in water (1 L) and addition of ammoniumhydroxide 30% (500 μL).

It will be apparent to the one skilled in the art that differentretention times may be obtained for LC data if different analyticalconditions are used.

Mass spectrometric measurements in LCMS mode are performed as follows:

-   -   For basic elution, analyses are performed using:

A QDA Waters simple quadrupole mass spectrometer is used for LCMSanalysis. This spectrometer is equipped with an ESI source and an UPLCAcquity Hclass with diode array detector (200 to 400 nm). Data areacquired in a full MS scan from m/z 70 to 800 in positive mode with anbasic elution. The reverse phase separation is carried out at 45° C. ona Waters Acquity UPLC BEHC18 1.7 μm (2.1×50 mm) column for basicelution. Gradient elution is done with water/ACN/ammonium formate(95/5/63 mg/L) (solvent A) and ACN/water/ammonium formate (95/5/63 mg/L)(solvent B). Injection volume: 1 μL. Full flow in MS.

Basic Program “4 Min”

Time (min) A (%) B (%) Flow (mL/min) 0 99 1 0.4 0.3 99 1 0.4 3.2 0 1000.4 3.25 0 100 0.5 4 0 100 0.5

Basic Program “10 Min”

Time (min) A (%) B (%) Flow (mL/min) 0 99 1 0.4 0.8 99 1 0.4 5.3 0 1000.4 5.35 0 100 0.5 7.30 0 100 0.5

-   -   For acidic elution, analyses are performed using:

A QDA Waters simple quadrupole mass spectrometer is used for LCMSanalysis. This spectrometer is equipped with an ESI source and an UPLCAcquity Hclass with diode array detector (200 to 400 nm). Data areacquired in a full MS scan from m/z 70 to 800 in positive mode with anacidic elution. The reverse phase separation is carried out at 45° C. ona Waters Acquity UPLC HSS T3 1.8 μm (2.1×50 mm) column for acidicelution. Gradient elution is done with water/ACN/TFA (95/5/0.5 mL/L)(solvent A) and ACN (solvent B). Injection volume: 1 μL. Full flow inMS.

Acidic Program “4 Min”

Time (min) A (%) B (%) Flow (mL/min) 0 99 1 0.4 0.3 99 1 0.4 3.2 5 950.4 3.25 5 95 0.5 4 5 95 0.5

Acidic Program “10 Min”

Time (min) A (%) B (%) Flow (mL/min) 0 99 1 0.4 0.8 99 1 0.4 5.3 5 950.4 5.35 5 95 0.5 7.30 5 95 0.5

Crude materials could be purified by normal phase chromatography,(acidic or basic) reverse phase chromatography, chiral separation orrecrystallization.

Normal reverse phase chromatography are performed using silica gelcolumns (100:200 mesh silica gel or Puriflash®-50SIHC-JP columns fromInterchim).

Preparative Reverse Phase Chromatography are Performed as Follows:

-   -   LCMS purification (Basic mode, LCMS prep) using a SQD or QM        Waters triple quadrupole mass spectrometer is used for LCMS        purification. This spectrometer is equipped with an ESI source        and a Prep LC controller Waters quaternary pump with diode array        detector (210 to 400 nm).

MS Parameters:

ESI capillary voltage 3 kV. Cone and Extractor voltage 10. Source blocktemperature 120° C. Desolvation temperature 300° C. Cone gaz flow 30 L/h(Nitrogen), Desolvation Gas flow 650 L/h. Data are acquired in a full MSscan from m/z 100 to 700 in positive mode with an acidic or a basicelution.

LC Parameters:

The reverse phase separation is carried out at rt on a XBridge prep OBDC18 column (5 μm, 30×50 mm) (basic elution). Gradient elution is donewith Water (solvent A), ACN (solvent B), Ammonium bicarbonate in water 8g/L+500 μL/L NH₄OH 30% (solvent C) (pH-8.5). HPLC flow rate: 35 mL/minto 60 mL/min, injection volume: 1 mL. The splitting ratio is set at+/−1/6000 to MS.

Time (min) A (%) B (%) C (%) Flow (mL/min) 0 85 5 10 35 1 85 5 10 35 7 585 10 35 9 5 95 0 60 12 5 95 0 60 12.5 85 5 10 35 16 85 5 10 35

Preparative Chiral Chromatographic separations are performed on usingliquid phase chromatography or supercritical fluid chromatography (SFC)instruments with various mixtures of lower alcohols and C₅ to C₈ linear,branched or cyclic alkanes at 360 mL/min. Solvent mixtures as well ascolumns are described in individual procedures.

Products were generally dried under vacuum before final analyses andsubmission to biological testing.

NMR spectra are recorded on a BRUKER AVANCEIII 400 MHz-Ultrashield NMRSpectrometer fitted with a Windows 7 Professional workstation runningTopspin 3.2 software and a 5 mm Double Resonance Broadband Probe (PABBI1H/19F-BB Z-GRD Z82021/0075) or a 1 mm Triple Resonance Probe (PATXI1H/D-13C/15N Z-GRD Z868301/004). The compounds were studied in DMSO-d₆,or CDCl₃ solution at a probe temperature of 300 K and at a concentrationof 10 mg/mL. The instrument is locked on the deuterium signal ofDMSO-d₆, or CDCl₃. Chemical shifts are given in ppm downfield from TMS(tetramethylsilane) taken as internal standard.

Optical rotations ([α]_(D)) were measured on a PERKIN-ELMER polarimeter341 in a cuvette (I=1 dm) at a 10 mg/mL concentration, at a temperaturementioned in the specific examples, at 589 nm (sodium lamp).

The following examples illustrate how the compounds covered by formula(I) may be synthesized. They are provided for illustrative purposes onlyand are not intended, nor should they be construed, as limiting theinvention in any manner. Those skilled in the art will appreciate thatroutine variations and modifications of the following examples can bemade without exceeding the spirit or scope of the invention.

Example 1. Synthesis of(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one1 and(+3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one2

1.1 Synthesis of 1-nitropentan-2-ol I

A mixture of butyraldehyde (CAS: 123-72-8, 1 eq., 5.0 g, 69.3 mmol) andpotassium carbonate (1 eq., 9.68 g, 69.3 mmol) in nitromethane (95 mL)was stirred at 50° C. for 5 h. The mixture was cooled to roomtemperature and ethyl acetate was added (100 mL). The organic layer waswashed with water (two times), dried over MgSO₄, filtered and evaporatedto dryness to give a brown oil. The crude mixture was purified by flashchromatography Biotage Isolera Four (100 g KP-SNAP silica gel columnwith 100% dichloromethane over 12 CV) and the pure fractions wereevaporated to dryness to give 1-nitropentan-2-ol 1 (4.7 g, 35.0 mmol) asa colorless oil.

Yield: 51%

¹H NMR (400 MHz, DMSO-d₆): δ 5.26 (d, J=6.2 Hz, 1H), 4.64 (dd, J=12.2,3.2 Hz, 1H), 4.31 (dd, J=12.1, 9.3 Hz, 1H), 4.09 (ddt, J=8.9, 5.9, 3.2Hz, 1H), 1.47-1.23 (m, 4H), 0.95-0.77 (m, 3H).

1.2 Synthesis of 1-aminopentan-2-ol II

A solution of 1-nitropentan-2-ol I (1 eq., 200 mg, 1.5 mmol) in ethanol(8 mL) was hydrogenated on a 10% Pd/C cartridge, at 50° C., under H₂pressure (50 bar) in a H-Cube reactor during 1 h (flow: 1 mL/min, 7.5cycles). The crude mixture was evaporated to dryness and dried underhigh vacuum to give 1-aminopentan-2-ol II (140 mg, 1.22 mmol,) ascolorless oil. The obtained crude compound was used directly in the nextstep without any further purification.

Yield: 81%

¹H NMR (400 MHz, DMSO-d₆) δ 3.37-3.25 (m, 1H), 2.52 (d, J=4.1 Hz, 1H),2.37 (dd, J=12.6, 7.3 Hz, 1H), 1.45-1.20 (m, 4H), 0.93-0.79 (m, 3H).

1.3 Synthesis of 5-propyloxazolidin-2-one III

To a solution of 1-aminopentan-2-ol II (1 eq., 1.0 g, 9.2 mmol) and1,1′-carbonyldiimidazole (1 eq., 1.6 g, 9.7 mmol) in THF (20 mL) wasadded sodium hydride (0.1 eq., 23 mg, 0.92 mmol) and the mixture wasstirred at 25° C. during 24 h. Ethyl acetate and water were added to thereaction mixture and the aqueous layer was extracted with ethyl acetate(two times), washed with water and brine, dried over MgSO₄, filtered andevaporated to dryness to give a yellow oil. The crude was purified byflash chromatography Biotage Isolera Four (50 g KP-SNAP silica gelcolumn in a gradient of 0% to 10% methanol in dichloromethane over 10CV) and the pure fractions were evaporated to dryness to give5-propyloxazolidin-2-one III (990 mg, 7.59 mmol) as a white solid.

Yield: 82%

LC/MS: [M+H]⁺=130.1

¹H NMR (400 MHz, CDCl₃): δ 5.98 (s, 1H), 4.73-4.55 (m, 1H), 3.65 (td,J=8.4, 0.8 Hz, 1H), 3.22 (ddd, J=8.2, 7.2, 0.9 Hz, 1H), 1.87-1.70 (m,1H), 1.69-1.32 (m, 3H), 0.96 (t, J=7.3 Hz, 3H).

1.4 Synthesis of[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolV

In a sealed tube,2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole IV(CAS: 1294001-16-3, patent application WO 2012/143117, 1 eq., 2.0 g, 8.4mmol), paraformaldehyde (6.0 eq., 1.52 g, 50.6 mmol) and an aqueoussolution of hydrochloric acid (2N) (1.0 equiv., 4.2 mL, 8.4 mmol) weremixed in 1,4-dioxane (4 mL). The mixture was stirred at 100° C. for 18 hand the reaction was checked by LC/MS. The crude mixture was cooled toRT and an aqueous saturated solution of NaHCO₃ was added until pH=6-7.The aqueous layer was extracted with ethyl acetate (three times) and thecombined organic layers were washed with brine, dried over MgSO₄,filtered and evaporated to dryness. The crude was purified by flashchromatography Biotage Isolera Four (100 g KP-SNAP silica gel column ina gradient of 0% to 10% methanol in dichloromethane over 15 CV) to give[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol(1.06 g, 3.5 mmol) V as a beige solid. The compound was used directly inthe next step without any further purification.

Yield: 41%

LC/MS: [M+H]+=268.2

¹H NMR (400 MHz, CDCl₃): δ 5.04 (d, J=5.2 Hz, 2H), 4.77 (s, 2H), 3.53(s, 3H), 2.32 (t, J=6.3 Hz, 1H).

1.5 Synthesis of(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one1 and(−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one2

To a mixture of[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolV (1 eq., 200 mg, 0.74 mmol) and 5-propyloxazolidin-2-one III (2 eq.,190 mg, 1.48 mmol) in sulfolane (3 mL), was added p-toluenesulfonic acidmonohydrate (1 eq., 152 mg, 0.74 mmol) and the mixture was stirred at110° C. for 16 h. The crude mixture was directly purified by reversephase preparative HPLC (basic conditions) to give a beige solid (155 mgof the racemate) which was purified by chiral SFC (Phase WhelkO1 (R,R),50×227 mm/CO₂/EtOH Co-solvent 20%/30° C./360 mL/min). The purestfractions were evaporated to dryness to give(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one1 (first eluted, 56 mg, 0.15 mmol) and(−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one2 (second eluted, 56 mg, 0.15 mmol) as colorless oils.

Yields: 20%

LC/MS: [M+H]⁺=379.4

¹H NMR (400 MHz, DMSO-d₆): δ 4.84 (s, 2H), 4.74 (qd, J=15.8, 1.2 Hz,2H), 4.44 (dtd, J=8.3, 7.0, 5.4 Hz, 1H), 3.54 (t, J=8.3 Hz, 1H), 3.43(s, 3H), 3.08 (dd, J=8.4, 6.9 Hz, 1H), 1.62-1.45 (m, 2H), 1.28 (dddd,J=16.1, 13.6, 8.4, 4.0 Hz, 1H), 0.85 (t, J=7.4 Hz, 3H).

Alpha-D (1, MeOH, 10 mg/mL, 26.5° C.)=+27.0

Alpha-D (2, MeOH, 10 mg/mL, 26.5° C.)=−26.2

Example 2.(+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one3 and(+3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one4

1.5 Synthesis of6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1b][1,3,4]thiadiazole VII

To a solution of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine VI (CAS:15884-86-3, 1.0 eq., 6.5 g, 45 mmol) in DMF (100 mL), at 100° C., wasadded dropwise a solution of 3-bromo-1,1-difluoro-propan-2-one (CAS:883233-85-0, 1.05 eq., 8.1 g, 47 mmol) in DMF (5 mL). The reactionmixture was heated at 100° C. during 3 h and the completion was checkedby LC/MS. A saturated aqueous solution of NaHCO₃ was added and theorganic layer was extracted with ethyl acetate (three times). Thecombined organic layers were washed with water (five times), dried overMgSO₄, filtered and evaporated to dryness to give a brown solid (7.6 g).The crude was purified by flash chromatography Biotage Isolera Four (100g KP-SNAP silica gel column in a gradient of 0% to 5% methanol indichloromethane over 12 CV) and the pure fractions were evaporated underhigh vacuum to give6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole VII(3.95 g, 17.8 mmol) as an orange solid.

Yield: 40%

LC/MS: [M+H]+=220.2

¹H NMR (400 MHz, DMSO-d₆): δ 8.53 (t, J=2.2 Hz, 1H), 7.01 (t, J=54.6 Hz,1H), 4.83 (s, 2H), 3.43 (s, 3H).

1.6 Synthesis of[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolVIII

In a sealed tube,6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole VII(1.0 eq., 3.95 g, 18.0 mmol), paraformaldehyde (6.0 eq., 3.24 g, 108mmol) and an aqueous solution of hydrochloric acid (2N) (0.9 equiv., 8.1mL, 16.2 mmol) were mixed in 1,4-dioxane (8 mL). The mixture was stirredat 100° C. for 3.5 h and the reaction was checked by LC/MS. The crudemixture was cooled to RT and an aqueous saturated solution of NaHCO₃ wasadded until pH=6-7. The aqueous layer was extracted with ethyl acetate(three times) and the combined organic layers were washed with brine,dried over MgSO₄, filtered and evaporated to dryness. The crude waspurified by flash chromatography Biotage Isolera Four (100 g KP-SNAPsilica gel column in a gradient of 0% to 10% methanol in dichloromethaneover 15 CV) to give a yellow oil (3 g) which was purified a second timeby reverse phase HPLC (KROMASIL-Eternity XT C₁₈ 10 μm/ACN/H₂O/NH₄OHgradient from 20/80/0.1 to 50/50/0.1). The purest fractions wereevaporated to dryness to give[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolVIII (2 g, 8.02 mmol) as a white solid.

Yield: 45%

LC/MS: [M+H]+=250.2

¹H NMR (400 MHz, DMSO-d₆): δ 7.11 (t, J=53.6 Hz, 1H), 5.47 (t, J=5.4 Hz,1H), 4.84 (s, 2H), 4.79 (d, J=5.5, Hz, 2H), 3.44 (d, J=0.9 Hz, 3H).

1.7. Synthesis of(+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one3 and(−)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one4

To a mixture of[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolVIII (1 eq., 200 mg, 0.8 mmol) and 5-propyloxazolidin-2-one III (2 eq.,206 mg, 1.6 mmol) in sulfolane (3 mL), was added p-toluenesulfonic acidmonohydrate (1 eq., 152 mg, 0.8 mmol) and the mixture was stirred at110° C. for 3.5 h. The crude mixture was directly purified by reversephase preparative HPLC (basic conditions) to give a beige solid (216 mgof the racemate) which was purified by chiral SFC (Phase WhelkO1 (R,R),50×227 mm/CO₂/EtOH Co-solvent 20%/30° C./360 mL/min). The purestfractions were evaporated to dryness to give(+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one3 (first eluted, 54 mg, 0.15 mmol, 19% yield) and(−)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one4 (second eluted, 52 mg, 0.14 mmol, 18% Yield) as colorless oils.

Yields: 19% (3) and 18% (4)

LC/MS: [M+H]+=361.4

¹H NMR (400 MHz, DMSO-d₆): δ 7.12 (t, J=53.5 Hz, 1H), 4.83 (d, J=0.9 Hz,2H), 4.81-4.66 (m, 2H), 4.46 (dtd, J=8.4, 7.0, 5.5 Hz, 1H), 3.56 (t,J=8.4 Hz, 1H), 3.44 (s, 3H), 3.09 (dd, J=8.4, 7.0 Hz, 1H), 1.65-1.42 (m,2H), 1.39-1.17 (m, 2H), 0.86 (t, J=7.3 Hz, 3H).

Alpha-D (3, MeOH, 10 mg/mL, 27.7° C.)=+17.2

Example 3. Synthesis of(+)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one5 and(−)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one6

3.1 Synthesis of[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolX

A solution of2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazoleIX (WO2011047860, 1.0 eq., 1.25 g, 5.24 mmol), paraformaldehyde (6.0equiv., 943 mg, 31.45 mmol) and hydrochloric acid (1.0 eq., 2.6 mL, 5.24mmol) in 1,4-dioxane (2.6 mL) was stirred at 100° C. during 18 h. Asaturated aqueous solution of NaHCO₃ was added and the aqueous layer wasextracted with ethyl acetate (3 times). The combined organic layers werewashed with brine, dried over MgSO₄, filtered and evaporated to drynessto give a yellow oil. The obtained crude was purified by flashchromatography Biotage Isolera Four (50 g KP-SNAP silica gel column from100% dichloromethane to 10% methanol in dichloromethane over 15CV) togive a brown solid which was purified via reverse phase chromatographyin basic mode. The purest fraction were evaporated to dryness to give[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolX (475 mg, 1.73 mmol) as a white solid.

Yield: 33%

LC/MS: [M+H]⁺=270.01

¹H NMR (400 MHz, DMSO-d6): δ 5.56 (s, 1H), 4.77 (s, 2H), 3.44 (s, 3H).

3.2 Synthesis of(+)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one5 and(−)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one6

To a mixture of[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolX (1.0 eq., 200 mg, 0.74 mmol) and 5-propyloxazolidin-2-one III (2.0eq., 190 mg, 1.47 mmol) in sulfolane (0.2 M, 3.5 mL), was addedp-toluenesulfonic acid monohydrate (1.0 eq., 140 mg, 0.73 mmol) and themixture was stirred at 110° C. for 16 h. The crude was directly purifiedby reverse phase chromatography in basic conditions to give of a yellowoil (172 mg). The mixture of enantiomers was purified via chiral SFC (W(3 μm)*EtOH 50%-heptane 50%-DEA 0.1%) to give(+)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one5 (75 mg, 0.20 mmol) and(−)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one6 (72 mg, 0.19 mmol) as colorless oils.

Global yield: 52% (26.5%+25.5%)

LC/MS: [M+H]⁺=381.11

¹H NMR (400 MHz, CDCl₃): δ 5.00-4.75 (m, 2H), 4.51-4.40 (m, 1H), 3.51(s, 4H), 3.04 (dd, J=8.4, 7.4 Hz, 1H), 1.76-1.66 (m, 1H), 1.60-1.50 (m,1H), 1.48-1.29 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

Alpha-D (5, MeOH, 10 mg/mL, 25° C.)=+17.6

Example 4. Synthesis of(+)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one7 and(−)-3-[[2-[deuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one8

4.1 Synthesis of-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazoleXII

To a solution ofdideuterio-[6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]methanolXI (WO2011047860, 1.0 eq., 3.25 g, 13.0 mmol) in methanol (100 mL), atroom temperature, was added silver oxide (1.3 eq., 3.9 g, 16.9 mmol) andiodomethane-d3 (4.0 eq., 3.23 mL, 52.0 mmol). The reaction mixture wasstirred at 40° C. during 20 h. The mixture was then filtered through apad of Celite and evaporated to dryness. A saturated aqueous solution ofNaHCO₃ was added and the aqueous layer was extracted with ethyl acetate(3 times). The combined organic layers were dried over MgSO₄, filteredand evaporated to dryness to give a yellow oil which was purified byflash chromatograpy Biotage Isolera Four (100 g KP-SNAP silica gelcolumn from 100% dichloromethane to 5% methanol in dichloromethane over15CV) to give2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazoleXII (2.11 g, 7.4 mmol) as a white solid.

Yield: 57%

LC/MS: [M+H]+=243.08

¹H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H).

4.2 Synthesis of[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolXIII

A solution of2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazoleXII (1.0 eq., 1.0 g, 4.1 mmol), paraformaldehyde (6.0 eq., 743 mg, 24.7mmol) and hydrochloric acid (1.0 eq., 4.1 mmol, 2.0 mL) in 1,4-dioxane(2 mL) was stirred at 100° C. during 18 h. A saturated aqueous solutionof NaHCO₃ was added and the aqueous layer was extracted with ethylacetate (3 times). The combined organic layers were washed with brine,dried over MgSO₄, filtered and evaporated to dryness to give a yellowoil which was purified via reverse phase chromatography in basic mode.The purest fraction were evaporated to dryness to give[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolXIII (560 mg, 1.97 mmol) as a white solid.

Yield: 48%

LC/MS: [M+H]+=270.01

¹H NMR (400 MHz, DMSO-d6): δ 5.30-6.30 (br s, 1H) 4.77 (d, J=1.3 Hz,2H).

4.3 Synthesis of(+)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one7 and(−)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one8

To a mixture of[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolXIII (1.0 eq., 200 mg, 0.73 mmol) and 5-propyloxazolidin-2-one III (2.0eq., 190 mg, 1.47 mmol) in sulfolane (0.2 M, 3.5 mL), was addedp-toluenesulfonic acid monohydrate (1.0 eq., 101 mg, 0.53 mmol) and themixture was stirred at 110° C. for 16 h. The crude was purified byreverse phase chromatography in basic conditions to give of a yellow oil(175 mg). The mixture of enantiomers was purified by chiral SFC (W (3μm)*EtOH 50%-heptane 50%-DEA 0.1%) to give(+)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one7 (47 mg, 0.12 mmol) and(−)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one8 (51 mg, 0.13 mmol) as clear oils.

Global Yield: 35% (17%+18%)

LC/MS: [M+H]⁺=384.14

¹H NMR (400 MHz, CDCl₃): δ 4.95 (dd, J=15.7, 1.2 Hz, 1H), 4.79 (dd,J=15.6, 1.2 Hz, 1H), 4.47 (qd, J=7.7, 5.2 Hz, 1H), 3.49 (t, J=8.4 Hz,1H), 3.13-2.95 (m, 1H), 1.70 (dddd, J=12.8, 9.6, 7.5, 5.2 Hz, 1H),1.57-1.49 (m, 1H), 1.48-1.28 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

Alpha-D (7, MeOH, 10 mg/mL, 25° C.)=+26.9

Example 5. Synthesis of give(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one9 and(−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one10

5.1 Synthesis of 4,4,4-trifluoro-1-nitro-butan-2-ol XIV

A mixture of 3,3,3-trifluoropropanal (1.0 eq., 5.0 g, 44.62 mmol),potassium carbonate (1.0 eq., 6.2 g, 44 mmol) and nitromethane (30 eq.,60.2 mL, 1340 mmol) was stirred at 50° C. for 5 h. The mixture wascooled to room temperature and diluted with water and ethyl acetate. Theaqueous layer was extracted with ethyl acetate (3 times) and thecombined organic layers were washed with water (2 times), dried overMgSO₄, filtered and evaporated to dryness. The crude was purified byflash chromatography Biotage Isolera Four (100 g KP-SNAP silica gelcolumn gradient: 100% dichloromethane over 10 CV). The purest fractionswere evaporated to dryness to give 4,4,4-trifluoro-1-nitro-butan-2-olXIV (3.8 g, 22 mmol) as a colorless oil.

Yield: 49%

¹H NMR (400 MHz, CDCl₃): δ 4.73 (dddd, J=12.7, 7.6, 5.0, 3.8 Hz, 1H),4.58-4.43 (m, 2H), 3.01 (d, J=5.1 Hz, 1H), 2.60-2.28 (m, 2H).

5.2 Synthesis of 1-amino-4,4,4-trifluoro-butan-2-ol XV

A mixture of 4,4,4-trifluoro-1-nitro-butan-2-ol XIV (1.0 eq., 4.8 g, 28mmol) in ethanol (140 mL) was hydrogenated using a H-cube reactorequipped with a Raney Ni cartridge (flow 1 mL/min, 50° C., 50 bar). Themixture was evaporated to dryness to give1-amino-4,4,4-trifluoro-butan-2-ol XV (2.5 g, 17 mmol) as a colorlessoil.

Yield: 63%

¹H NMR (400 MHz, CDCl₃): δ 3.89 (tt, J=8.0, 3.9 Hz, 1H), 2.86 (dd,J=12.8, 3.5 Hz, 1H), 2.62 (dd, J=12.8, 8.3 Hz, 1H), 2.35-2.07 (m, 2H).

5.3 Synthesis of 5-(2,2,2-trifluoroethyl)oxazolidin-2-one XVI

To a mixture of 1-amino-4,4,4-trifluoro-butan-2-ol XV (1.0 eq., 2.5 g,17 mmol) and 1,1′-carbonyldiimidazole (1.0 eq., 2.9 g, 18 mmol) in THF(35 mL) was added sodium hydride (0.1 eq., 42 mg, 1.75 mmol) and themixture was stirred at 25° C. for 16 h. A few drops of water were added(NaH neutralization) and the mixture was directly evaporated to drynessand purified by reverse phase chromatography in basic mode to give5-(2,2,2-trifluoroethyl)oxazolidin-2-one XVI (2.25 g, 13.2 mmol) as awhite solid

Yield: 75%

LC/MS: [M+H]⁺=170.11

¹H NMR (400 MHz, DMSO-d6): δ 7.61 (s, 1H), 4.81 (qd, J=7.6, 4.9 Hz, 1H),3.62 (t, J=8.7 Hz, 1H), 3.20 (dd, J=8.9, 7.2 Hz, 1H), 2.89-2.68 (m, 2H).

5.4 Synthesis of(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one9 and(−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one10

To a mixture of[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolV (1.0 eq., 200 mg, 0.75 mmol) and5-(2,2,2-trifluoroethyl)oxazolidin-2-one XVI (1.8 eq., 227 mg, 1.34mmol) in sulfolane (0.5 M, 3.7 mL), was added p-toluenesulfonic acidmonohydrate (1.0 eq., 142 mg, 0.75 mmol) and the mixture was stirred at110° C. for 3 h 30. The mixture was directly purified via reverse phasechromatography in basic conditions to give a yellow oil (250 mg). Theobtained mixture of enantiomers was purified by chiral preparative HPLC(AS*EtOH 50%-heptane 50%-DEA 0.1%) to give(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one9 (29 mg, 0.07 mmol) and(−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one10 (30 mg, 0.07 mmol).

Global yield: 19% (9.3%+9.6%)

LC/MS: [M+H]⁺=419.05

¹H NMR (400 MHz, CDCl₃): δ 5.02-4.66 (m, 5H), 3.66 (t, J=8.7 Hz, 1H),3.52 (s, 3H), 3.33-3.17 (m, 1H), 2.76-2.58 (m, 1H), 2.51-2.35 (m, 1H).

Alpha-D (9, MeOH, 10 mg/mL, 25° C.)=+13.0

(+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one11 and(−)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one12 are synthesized according to the same procedure starting from5-(2,2,2-trifluoroethyl)oxazolidin-2-one XVI and[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolVIII.

Global yield: 14% (7.8%+6.2%)

LC/MS: [M+H]⁺=401.06

¹H NMR (400 MHz, DMSO-d6): δ 7.14 (t, J=53.5 Hz, 1H), 4.90-4.60 (m, 5H),3.67 (t, J=8.6 Hz, 1H), 3.43 (s, 3H), 3.25 (dd, J=8.6, 7.0 Hz, 1H),2.91-2.63 (m, 2H).

Alpha-D (11, MeOH, 10 mg/mL, 25° C.)=+3.6

Example 6. Synthesis of give(−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one13 and(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one14

6.1 Synthesis of 4,4-difluoro-1-nitro-pentan-2-ol XVII

To a solution of 3,3-difluorobutan-1-ol (1.0 eq., 1.5 g, 9.8 mmol) indichloromethane (50 mL) at 0° C. was added Dess-Martin periodinane (1.2eq., 5.1 g, 12 mmol) and the reaction mixture was stirred at 0° C.during 2 h. The crude mixture was then cooled to −78° C., filtered andthe obtained solid was washed with cold dichloromethane (−78° C.). Tothe obtained filtrate warmed at room temperature was added potassiumcarbonate (15.0 eq., 21 g, 150 mmol) and nitromethane (30.0 eq., 18 g,290 mmol) and the mixture was stirred at 45° C. during 2 h. The crudemixture was filtered on Celite and the obtained filtrate wasconcentrated under vacuum at 30° C. to give a yellow gum. The obtainedgum was purified by flash chromatography Biotage Isolera Four (100 gKP-SNAP silica gel column in a gradient 100% dichloromethane over 6CVthan 0% to 10% methanol in dichloromethane over 10CV) to give4,4-difluoro-1-nitro-pentan-2-ol XVII (678 mg, 4.0 mmol) as a yellowoil.

Yield: 41%

¹H NMR (400 MHz, CDCl₃): δ 4.71 (tt, J=7.9, 4.0 Hz, 1H), 4.61-4.36 (m,2H), 2.79 (dd, J=4.6, 1.7 Hz, 1H), 2.32-2.03 (m, 2H), 1.71 (t, J=18.9Hz, 3H).

6.2 Synthesis of 1-amino-4,4-difluoro-pentan-2-ol XVIII

A solution of 4,4-difluoro-1-nitro-pentan-2-ol XVII (1.0 eq., 1 g, 5.91mmol) in ethanol (40 mL) was hydrogenated in a H-Cube equipped with a10%/Pd cartridge (flow 1 mL/min, 50° C., 50 bar).The crude mixture wasevaporated to dryness to give 1-amino-4,4-difluoro-pentan-2-ol XVIII(760 mg, 4.9 mmol) as a colorless oil.

Yield: 83%

¹H NMR (400 MHz, CDCl₃): δ 3.95-3.76 (m, 1H), 2.88 (dd, J=12.7, 3.6 Hz,1H), 2.58 (dd, J=12.7, 8.2 Hz, 1H), 2.16-1.88 (m, 2H), 1.69 (t, J=18.9Hz, 3H).

6.3 Synthesis of 5-(2,2-difluoropropyl)oxazolidin-2-one XIX

To a solution of 1-amino-4,4-difluoro-pentan-2-ol XVIII (1.0 eq., 760mg, 5.46 mmol) in THF (18 mL) at room temperature were added1,1′-carbonyldiimidazole (1.0 eq., 876 mg, 5.30 mmol) and sodium hydride(0.1 eq., 21 mg, 0.53 mmol). The reaction was stirred at roomtemperature during 16 h. A few drops of water were added to the solution(NaH neutralization) and the mixture was evaporated to dryness. Thecrude was directly purified by flash chromatography Biotage Isolera Four(100 g KP-SNAP silica gel column in a gradient of 0% to 10% methanol indichloromethane over 10CV, than 10% of Methanol over 4CV) to give5-(2,2-difluoropropyl)oxazolidin-2-one XIX (675 mg, 4.08 mmol) as abeige solid.

Yield: 75%

¹H NMR (400 MHz, CDCl₃): δ 5.34 (d, J=37.0 Hz, 1H), 4.96-4.85 (m, 1H),3.78 (td, J=8.5, 8.0, 0.9 Hz, 1H), 3.37 (t, J=8.2 Hz, 1H), 2.56-2.18 (m,2H), 1.71 (t, J=18.9 Hz, 3H).

6.4 Synthesis of(+5-(2,2-difluoropropyl)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one13 and(+)-5-(2,2-difluoropropyl)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one14

To a mixture of[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolV (1.0 eq., 150 mg, 0.56 mmol) and5-(2,2-difluoropropyl)oxazolidin-2-one XIX (1.5 eq., 139 mg, 0.84 mmol)in sulfolane (3 mL), was added p-toluenesulfonic acid monohydrate (1.0eq., 106 mg, 0.56 mmol). The mixture was stirred for 16 h at 100° C. Themixture was directly purified by reverse phase chromatography in basicmode to give a yellow oil. The mixture of enantiomers was purified bychiral SFC (AS*EtOH 50%-heptane 50%-DEA 0.1%) to give(+5-(2,2-difluoropropyl)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one13 (19.1 mg, 0.05 mmol) and(+)-5-(2,2-difluoropropyl)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one14 (19.9 mg, 0.05 mmol) as white solids.

Global yield: 16.7% (8.2%+8.5%)

LC/MS: [M+H]⁺=415.02

¹H NMR (400 MHz, DMSO-d₆): δ 4.90-4.55 (m, 5H), 3.63 (t, J=8.4 Hz, 1H),3.45 (s, 3H), 3.22 (t, J=8.0 Hz, 1H), 2.42-2.26 (m, 2H), 1.63 (t, J=19.3Hz, 3H).

Alpha-D (13, MeOH, 10 mg/mL, 28.6° C.)=−13.3

3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2-difluoropropyl)oxazolidin-2-one15 and3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2-difluoropropyl)oxazolidin-2-one16 are synthesized according to the same procedure starting from5-(2,2-difluoropropyl)oxazolidin-2-one XIX and[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanolVIII.

Global yield: 8% (4%+4%)

LC/MS: [M+H]⁺=397.04

¹H NMR (400 MHz, DMSO-d6): δ 7.13 (t, J=53.5 Hz, 1H), 4.89-4.60 (m, 5H),3.64 (t, J=8.5 Hz, 1H), 3.43 (s, 3H), 3.21 (t, J=8.0 Hz, 1H), 2.41-2.17(m, 2H), 1.62 (t, J=19.3 Hz, 3H).

Chiral chromatography (SFC, phase W, CO₂-MeOH 15%, 3 ml/min): peak 1(15): 6.64 min and peak 2 (16): 7.72 min.

Table (I) indicates the IUPAC name (or the name generated from AccelerysDraw 4.0) of the compound, the ion peak observed in mass spectroscopyand the ¹H NMR description.

TABLE I Physical Characterization of Example Compounds. n° Compound NAMEStructure MH⁺ ¹H NMR δ (DMSO-d₆) 1 (+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl- oxazolidin-2-one

379.4 4.84 (s, 2H), 4.74 (qd, J = 15.8, 1.2 Hz, 2H), 4.44 (dtd, J = 8.3,7.0, 5.4 Hz, 1H), 3.54 (t, J = 8.3 Hz, 1H), 3.43 (s, 3H), 3.08 (dd, J =8.4, 6.9 Hz, 1H), 1.62-1.45 (m, 2H), 1.28 (dddd, J = 16.1, 13.6, 8.4,4.0 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H). 2 (−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl- oxazolidin-2-one

379.4 4.84 (s, 2H), 4.74 (qd, J = 15.8, 1.2 Hz, 2H), 4.44 (dtd, J = 8.3,7.0, 5.4 Hz, 1H), 3.54 (t, J = 8.3 Hz, 1H), 3.43 (s, 3H), 3.08 (dd, J =8.4, 6.9 Hz, 1H), 1.62-1.45 (m, 2H), 1.28 (dddd, J = 16.1, 13.6, 8.4,4.0 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H). 3 (+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1- b][1,3,4]thiadiazol-5- yl]methyl]-5-propyl-oxazolidin-2-one

361.4 5.00-4.75 (m, 2H), 4.51- 4.40 (m, 1H), 3.51 (s, 4H), 3.04 (dd, J =8.4, 7.4 Hz, 1H), 1.76-1.66 (m, 1H), 1.60- 1.50 (m, 1H), 1.48-1.29 (m,2H), 0.92 (t, J = 7.3 Hz, 3H). 4 (−)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1- b][1,3,4]thiadiazol-5- yl]methyl]-5-propyl-oxazolidin-2-one

361.4 5.00-4.75 (m, 2H), 4.51- 4.40 (m, 1H), 3.51 (s, 4H), 3.04 (dd, J =8.4, 7.4 Hz, 1H), 1.76-1.66 (m, 1H), 1.60- 1.50 (m, 1H), 1.48-1.29 (m,2H), 0.92 (t, J = 7.3 Hz, 3H). 5 (+)-3-[[2- [dideuterio(methoxy)methyl]-6- (trifluoromethyl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl- oxazolidin-2-one

381.1 5.00-4.75 (m, 2H), 4.51- 4.40 (m, 1H), 3.51 (s, 4H), 3.04 (dd, J =8.4, 7.4 Hz, 1H), 1.76-1.66 (m, 1H), 1.60- 1.50 (m, 1H), 1.48-1.29 (m,2H), 0.92 (t, J = 7.3 Hz, 3H). 6 (−)-3-[[2- [dideuterio(methoxy)methyl]-6- (trifluoromethyl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl- oxazolidin-2-one

381.1 5.00-4.75 (m, 2H), 4.51- 4.40 (m, 1H), 3.51 (s, 4H), 3.04 (dd, J =8.4, 7.4 Hz, 1H), 1.76-1.66 (m, 1H), 1.60- 1.50 (m, 1H), 1.48-1.29 (m,2H), 0.92 (t, J = 7.3 Hz, 3H). 7 (+)-3-[[2- [dideuterio(trideuteriomethoxy) methyl]-6- (trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl]methyl]-5-propyl- oxazolidin-2-one

384.1 4.95 (dd, J = 15.7, 1.2 Hz, 1H), 4.79 (dd, J = 15.6, 1.2 Hz, 1H),4.47 (qd, J = 7.7, 5.2 Hz, 1H), 3.49 (t, J = 8.4 Hz, 1H), 3.13-2.95 (m,1H), 1.70 (dddd, J = 12.8, 9.6, 7.5, 5.2 Hz, 1H), 1.57-1.49 (m, 1H),1.48-1.28 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 8 (−)-3-[[2- [dideuterio(trideuteriomethoxy) methyl]-6- (trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl]methyl]-5-propyl- oxazolidin-2-one

384.1 4.95 (dd, J = 15.7, 1.2 Hz, 1H), 4.79 (dd, J = 15.6, 1.2 Hz, 1H),4.47 (qd, J = 7.7, 5.2 Hz, 1H), 3.49 (t, J = 8.4 Hz, 1H), 3.13-2.95 (m,1H), 1.70 (dddd, J = 12.8, 9.6, 7.5, 5.2 Hz, 1H), 1.57-1.49 (m, 1H),1.48-1.28 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 9(+)-3-[[2-(methoxymethyl)-6- (trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl]methyl]-5-(2,2,2- trifluoroethyl)oxazolidin-2-one

419.0 5.02-4.66 (m, 5H), 3.66 (t, J = 8.7 Hz, 1H), 3.52 (s, 3H),3.33-3.17 (m, 1H), 2.76- 2.58 (m, 1H), 2.51-2.35 (m, 1H). 10(−)-3-[[2-(methoxymethyl)-6- (trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl]methyl]-5-(2,2,2- trifluoroethyl)oxazolidin-2-one

419.0 5.02-4.66 (m, 5H), 3.66 (t, J = 8.7 Hz, 1H), 3.52 (s, 3H),3.33-3.17 (m, 1H), 2.76- 2.58 (m, 1H), 2.51-2.35 (m, 1H). 11(+)-3-[[6-(difluoromethyl)-2- (methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl]methyl]-5-(2,2,2- trifluoroethyl)oxazolidin-2-one

401.0 7.14 (t, J = 53.5 Hz, 1H), 4.90-4.60 (m, 5H), 3.67 (t, J = 8.6 Hz,1H), 3.43 (s, 3H), 3.25 (dd, J = 8.6, 7.0 Hz, 1H), 2.91- 2.63 (m, 2H).12 (−)-3-[[6-(difluoromethyl)-2- (methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl]methyl]-5-(2,2,2- trifluoroethyl)oxazolidin-2-one

401.0 7.14 (t, J = 53.5 Hz, 1H), 4.90-4.60 (m, 5H), 3.67 (t, J = 8.6 Hz,1H), 3.43 (s, 3H), 3.25 (dd, J = 8.6, 7.0 Hz, 1H), 2.91- 2.63 (m, 2H).13 (−)-5-(2,2-difluoropropyl)-3- [[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one

415.0 4.90-4.55 (m, 5H), 3.63 (t, J = 8.4 Hz, 1H), 3.45 (s, 3H), 3.22(t, J = 8.0 Hz, 1H), 2.42- 2.26 (m, 2H), 1.63 (t, J = 19.3 Hz, 3H). 14(+)-5-(2,2-difluoropropyl)-3- [[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one

415.0 4.90-4.55 (m, 5H), 3.63 (t, J = 8.4 Hz, 1H), 3.45 (s, 3H), 3.22(t, J = 8.0 Hz, 1H), 2.42- 2.26 (m, 2H), 1.63 (t, J = 19.3 Hz, 3H). 153-[[6-(difluoromethyl)-2- (methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl]methyl]-5-(2,2- difluoropropyl)oxazolidin-2-one (enantiomer 1)

397.0 7.13 (t, J = 53.5 Hz, 1H), 4.89- 4.60 (m, 5H), 3.64 (t, J = 8.5Hz, 1H), 3.43 (s, 3H), 3.21 (t, J = 8.0 Hz, 1H), 2.41- 2.17 (m, 2H),1.62 (t, J = 19.3 Hz, 3H). 16 3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1- b][1,3,4]thiadiazol-5- yl]methyl]-5-(2,2-difluoropropyl)oxazolidin-2- one (enantiomer 2)

397.0 7.13 (t, J = 53.5 Hz, 1H), 4.89- 4.60 (m, 5H), 3.64 (t, J = 8.5Hz, 1H), 3.43 (s, 3H), 3.21 (t, J = 8.0 Hz, 1H), 2.41- 2.17 (m, 2H),1.62 (t, J = 19.3 Hz, 3H).

Example 7. Binding Assays to SV2A and SV2C

Human SV2A and SV2C proteins were expressed in human embryonic kidney(HEK) cells. HEK SV2A and HEK SV2C membrane preparations were preparedas described in Gillard et al (Eur. J. Pharmacol. 2006, 536, 102-108).To measure affinity of non-labelled compounds, competition experimentswere performed as follow: Membranes expressing SV2 proteins (5 to 15 μgproteins per assay) were incubated for 60 min at 37° C. with either[³H]-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide (5 nM) and/or[³H]-4R-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one(25 nM) in 0.2 ml of a 50 mM Tris-HCl buffer (pH 7.4) containing 2 mMMgCl₂, 0.1% dimethylsulfoxide and ten increasing concentrations ofnon-labelled test compound (0.1 nM to 10 μM). At the end of theincubation period, the membrane-bound radioligand was recovered by rapidfiltration through GF/C glass fiber filters pre-soaked in 0.1%polyethyleneimine. Membranes were washed with at least 4 times the assayvolume of ice-cold 50 mM Tris HCl buffer (pH 7.4). The filters weredried and the radioactivity determined by liquid scintillation. Theentire filtration step did not exceed 10 sec. Measured affinity pIC₅₀values were corrected to pKi according to Cheng and Prusoff (Biochem.Pharmacol. 1973, 22(23), 3099-3108).

Compounds of formula (I) according to the invention typically show pKiSV2A values of at least 6.5. and pKi SV2C values of at least 6.0.

Example 8. Seizure Models

Male NMRI mice (Charles River, Germany) weighing 22-32 g are used in allexperiments. The animals are kept on a 12/12-h light/dark cycle withlights on at 6:00 am and are housed at a temperature maintained at20-21° C. and at humidity of about 40%. The mice are housed in groups of10 per cage (Type III). All animals have free access to standard pelletfood and water before random assignment to experimental groupsconsisting of 10 mice each. All animal experiments are done according tothe National Rules on Animal Experiments and conducted in accordancewith the guidelines of the European Community Council directive2010/63/EU. A local ethical committee approved the experimentalprotocols.

8.1 6 Hz Seizure Model

The 6 Hz model is carried out according to a previously describedprotocol (Kaminski et al., Epilepsia (2004), 45, 864-867). Briefly,corneal stimulation (44 mA, 0.2 ms-duration monopolar rectangular pulsesat 6 Hz for 3 s) is delivered by a constant-current device (ECT Unit57800; Ugo Basile, Comerio, Italy). A drop of 0.4% oxybuprocainehydrochloride (Unicaine, Thea, France) is placed on the eyes beforeelectrical stimulation. During the stimulation, mice are manuallyrestrained and released into the observation cage (38×26×14 cm)immediately after the current application. The seizures are oftenpreceded by a brief period (˜2-3 s) of intense locomotor agitation (wildrunning and jumping). The animals then exhibit a “stunned” postureassociated with rearing, forelimb automatic movements and clonus,twitching of the vibrissae, and Strub-tail. At the end of the seizure,animals resume their normal exploratory behavior. The experimentalendpoint is protection against the seizure. The animal is considered tobe protected if it resumes its normal exploratory behavior within 7 sfrom the stimulation.

In vivo activities determined for test compounds are typically comprisedbetween 0.05 mg/kg and 20 mg/kg after single IP dosing.

8.2 Pentylenetetrazol (PTZ) Seizure Model

Pentylenetetrazol is used at the previously established CD97 dose of 89mg/kg; a convulsive dose inducing clonic convulsions of all fourextremities in 97% of mice (Klitgaard et al., Eur. J. Pharmacol. (1998),353, 191-206). Immediately following pentylenetetrazol injection themice are placed individually in Perspex cages and observed for thepresence of clonic convulsions in all four extremities and tonichindlimb extension during 60 min period.

In vivo activities determined for test compounds are typically comprisedbetween 0.5 mg/kg and 30 mg/kg after single IP dosing.

Example 9. Azamulin Assay

Cryopreserved human hepatocytes (pool of 20 donors, BSU batch fromCelsis/IVT/Bioreclamation) were thawed accordingly the provider'sinformation. Viability (trypan blue exclusion) was higher than 75%.Pre-incubations (250 μL of hepatocytes suspension at 2×10⁶hepatocytes/mL) were carried out with William's medium, containing 2 mMof glutamine and 15 mM of Hepes, in 48-well plates at +37° C., in anincubator (5% CO₂), under gentle agitation (vibrating agitator, Titramax100, ca 300 rpm) during 30 min. After the pre-incubation, the incubationwas initiated by adding to hepatocytes, 250 μL of culture medium (seecomposition above) containing UCB compound (1 μM) or midazolam (positivecontrol) with or without azamulin (6 μM—specific CYP3A4/5 inhibitor).Final concentrations of UCB compound and azamulin in the incubates are0.5 μM and 3 μM, respectively. The cell suspensions was rapidlyre-homogenized by 2 in-out pipetting. After 0, 30, 60, 120, 180 and 240minutes of incubation, reactions were stopped by transferring 50 μl ofincubates into the appropriate well from 96-well plate containing 50 μLof ice cold acetonitrile with ketoconazole 1 μM as internal standard.Before each sampling, cell incubates are re-homogenized by 2 in outpipetting.

Once the incubation is finished, 96-well plates are centrifuged at ca3700 rpm, +4° C., for 15 minutes. 50 μL of supernatants are transferredinto the wells of other deep well plates to which 150 μL of H₂OMillipore were added. These samples were are analyzed by microUPLC/HR-MS for parent disappearance and monitoring of metaboliteformation.

The CYP3A4/5 contribution known as fraction metabolized by CYP3A4/5(f_(m,CYP3A4/5)) was calculated for each compound from the ratio betweenCLint (based on parent parent drug disappearance) in absence and inpresence of azamulin, by using the following equation:

${Fm}_{{CYP}\; 3A\; 4\text{/}5} = {1 - \frac{{CL}_{{int}\mspace{14mu} {with}\mspace{14mu} {azamulin}}}{{CL}_{{int}\mspace{14mu} {without}\mspace{14mu} {azamulin}}}}$

Fraction metabolized by CYP3A4/5 (f_(m,CYP3A4/5)) of test compounds aretypically comprised between 0 and 40%.

1. 2-oxo-1,3-oxazolidinyl imidazothiadiazole derivatives according toformula (I), their geometrical isomers, enantiomers, diastereomers,isotopes and mixtures, or a pharmaceutically acceptable salt thereof,

wherein R¹ is a C₁₋₄ alkyl optionally substituted by one or more halogensubstituents; R² is a halogen atom, or a C₁₋₄ alkyl optionallysubstituted by one or more halogen atoms; R³ is a C₁₋₄ alkyl substitutedby an alkoxy substituent.
 2. A compound according to claim 1, wherein R¹is an i-butyl, a n-propyl, a 2,2-difluoropropyl, a2-chloro-2,2-difluoroethyl, a 2,2-difluoroethyl, a 2,2,2-trifluoroethylor a 2-fluoroethyl moiety.
 3. A compound according to claim 1, whereinR¹ is n-propyl, a 2,2-difluoropropyl, or a 2,2,2-trifluoroethyl moiety.4. A compound according to claim 1, wherein R² is a chlorine atom, adifluoromethyl moiety, or a trifluoromethyl moiety.
 5. A compoundaccording to claim 1, wherein R² is a difluoromethyl moiety or atrifluoromethyl moiety.
 6. A compound according to claim 1, wherein R³is a methoxymethyl, a [(²H₃)methyloxy]methyl, a methoxy(²H₂)methyl, or a[(²H₃)methyloxy](²H₂)methyl moiety.
 7. A compound according to claim 1,wherein R¹ is a n-propyl, a 2,2-difluoropropyl or a 2,2,2-trifluoroethylmoiety; R² is a difluoromethyl or a trifluoromethyl moiety; R³ is amethoxymethyl, a [(²H₃)methoxy]methyl, a [(²H₃)methoxy] (²H₂) methyl ora methoxy(²H₂) methyl moiety.
 8. A compound according to claim 1 whichis:(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;(−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;(+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;(−)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;(+)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;(−)-3-[[2-[dideuterio(methoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;(+)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;(−)-3-[[2-[dideuterio(trideuteriomethoxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-propyl-oxazolidin-2-one;(+)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one;(−)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one;(+)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one;(−)-3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2,2-trifluoroethyl)oxazolidin-2-one;(−)-5-(2,2-difluoropropyl)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one;(+)-5-(2,2-difluoropropyl)-3-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]oxazolidin-2-one;3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2-difluoropropyl)oxazolidin-2-one,enantiomer 1; or−3-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-5-(2,2-difluoropropyl)oxazolidin-2-one,enantiomer
 2. 9. (canceled)
 10. A pharmaceutical composition comprisingan effective amount of a compound according to claim 1 in combinationwith a pharmaceutically acceptable diluent or carrier.
 11. A method forthe treatment of epilepsy, epileptogenesis, seizure disorders, orconvulsions, comprising administering to a patient in need thereof aneffective amount of a compound or salt according to claim
 1. 12. Amethod according to claim 9, wherein the treatment is for refractoryseizures.
 13. A compound according to claim 2, wherein R² is a chlorineatom, a difluoromethyl moiety, or a trifluoromethyl moiety.
 14. Acompound according to claim 3, wherein R² is a difluoromethyl moiety ora trifluoromethyl moiety.
 15. A compound according to claim 2, whereinR³ is a methoxymethyl, a [(²H₃)methyloxy]methyl, a methoxy(²H₂)methyl,or a [(²H₃)methyloxy](²H₂)methyl moiety.
 16. A compound according toclaim 4, wherein R³ is a methoxymethyl, a [(²H₃)methyloxy]methyl, amethoxy(²H₂)methyl, or a [(²H₃)methyloxy](²H₂)methyl moiety.